Alzheimer's disease and other cognitive disorders have received much attention lately, yet treatments for these diseases have not been very successful. According to Melchiorre et al. (J. Med. Chem. (1993), 36, 3734-3737), compounds that selectively antagonize m2 muscarinic receptors, especially in relation to m1 muscarinic receptors, should possess activity against cognitive disorders. Baumgold et al. (Eur. J. Pharmacol., 251, (1994) 315-317) disclose 3-.alpha.-chloroimperialine as a highly selective m2 muscarinic antagonist.
The present invention is predicated on the discovery of a class of di-N-substituted piperazines and 1,4-di-substituted piperidines. Logemann et al. (Brit. J. Pharmacol. (1961), 17, 286-296) describe certain di-N-substituted piperazines, but these are different from the inventive compounds of the present invention. Furthermore, the compounds of Logemann et al. are not disclosed to have activity against cognitive disorders.
International Patent Publication Number WO93/08799 published May 13 1993 (Smith-Kline Beecham) discloses inter alia indane derivatives that are endothelin receptor antagonists and are (in part) of the following formula: ##STR2## wherein: R.sub.1 is --X(CH.sub.2).sub.n Ar or --X(CH.sub.2).sub.n R.sub.8 ;
R.sub.2 is H or Ar; PA1 P.sub.1 is --X(CH.sub.2).sub.n R.sub.8 ; PA1 P.sub.2 is --X(CH.sub.2).sub.n R.sub.8 or --XR.sub.9 Y; PA1 R.sub.8 is H, alkyl, alkenyl, alkynyl, CO.sub.2 H, CO.sub.2 alkyl, or CO.sub.2 Ar; PA1 R.sub.9 is alkyl, alkenyl or phenyl; PA1 R.sub.10 is H, alkyl (which may be substituted with CO.sub.2 H, CO.sub.2 alkyl or CO.sub.2 (CH.sub.2).sub.n Ar), alkenyl, phenyl, OH, alkoxy, S(O).sub.q alkyl, S(O).sub.q alkenyl, S(O).sub.q aryl, NH.sub.2, NHalkyl, N(alkyl).sub.2, F, Cl, Br, I, CF.sub.3, NHCHO, NHCOalkyl, --X(CH.sub.2).sub.n R.sub.8 or --XR.sub.9 Y; PA1 X is (CH.sub.2).sub.n, O, NH, Nalkyl, or S(O).sub.q ; PA1 Y is CH.sub.3 or X(CH.sub.2).sub.n Ar; PA1 Ar is a variety of substituted or unsubstituted heterocyclic and aromatic hydrocarbon groups, including piperidinyl and piperazinyl, which may carry substituents; PA1 Z.sub.1 and Z.sub.2 are independently H, alkyl, alkenyl, alkynyl, OH, alkoxy, S(O).sub.q alkyl, NH.sub.2, NHalkyl, N(alkyl).sub.2, F, Cl, Br, I, CF.sub.3, NHCHO, NHCOalkyl, --X(CH.sub.2).sub.n R.sub.8, phenyl, benzyl or cycloalkyl; PA1 Z.sub.3 is Z.sub.1 or --XR.sub.9 Y; PA1 n is 0 or an integer from 1 to 6, and q is 0, 1 or 2; PA1 and the groups designated as `alkyl`, `alkenyl`, `alkynyl` or `phenyl` can all be substituted. PA1 one container contains a compound of formula I as defined above, including stereoisomers, pharmaceutically acceptable salts, esters, and solvates thereof, said compound being capable of enhancing acetylcholine release (and preferably being an m2 or m4 selective muscarinic antagonist) in a pharmaceutically acceptable carrier, and PA1 a second container contains an acetylcholinesterase inhibitor in a pharmaceutically acceptable carrier, PA1 the combined quantities being an effective amount. PA1 R is a phenyl group, which may be substituted with nitro or especially with methoxy, where each of these groups is preferably in the 4-position, or in particular a 2-pyrimidinyl group; PA1 X is S, SO, or especially SO.sub.2 or O; PA1 Q is O or especially CH.sub.2 ; PA1 n is 1 or 2 or especially 0; PA1 R.sup.1 is H and R.sup.21 is cyclohexylmethyl; PA1 R.sup.27 and R.sup.28 are CH.sub.3 or especially H; PA1 Z is N; and PA1 R.sup.2 is cyclohexyl or 1-piperidinyl.
(The definitions of radicals as given in that patent do not in general pertain to the present invention, even though similar symbols may be used.)